Medically unexplained chronic widespread pain (uCWP) is a common and disabling symptom that can even affect children and young adults, leaving some disabled from school or work. UCWP in the young can disrupt entire families and cause life-long handicap. UCWP syndromes go by various names including fibromyalgia. In 2013 we published a retrospective study of 41 of our patients with uCWP that began before age 21. We reported that most had objective evidence of small-fiber polyneuropathy (SFPN), a biologically plausible cause of their symptoms. The most useful test was PGP9.5 immunolabeled skin biopsies, which permit quantitation of small-fiber nerve ending density. Some patients appeared to have dysimmune causes of their SFPN, but this was far from certain. The goal of the proposed research is to rigorously test our hypothesis that SFPN is a common cause of CWP in children and young adults and that many have evidence of dysimmune causes. Our observations need prospective testing in a larger community-based sample with determination of best methods for diagnosis of early-onset small-fiber polyneuropathy (SFPN) and assessment of how to monitor patients over time. The tests used to diagnose SFPN are not widely available, and have not been normed for young patients. We provide evidence that more than half of SFPN patients under age 35 receive false-negative diagnoses when they are based on data from older normal adults with far fewer axons. This project addresses the clinical need for better evidence-based methods for diagnosing SFPN in young people with uCWP who currently have few options. It should have immediate, widespread clinical impact. It will also lay foundations for research including treatment trials an basic investigation of mechanisms. Both require rigorously diagnosed and longitudinally well-characterized patients, which this project should provide. Aim 1 proposes to identify the best objective tests for early onset SFPN in young patients with CWP and in positive and negative controls recruited from the community. We will focus on the recommended tests, autonomic function testing and skin biopsy, but will also investigate less invasive or cheaper tests such as in vivo corneal confocal microscopy, the Minor starch-iodine sweat test, a new questionnaire, and Sudoscan, a new sweat-measuring device. The goal is to develop the best tests that can be applied in diverse circumstances, including low-resource settings. Aim 2 will more rigorously define the medical causes of SFPN using laboratory blood tests and dermatopathologic study of skin biopsies in community-based cohorts. We will also see if these tests support our prior finding that half of people with early-onset uCWP have evidence of SFPN. Aim 3 will apply the questionnaire and best tests developed above at defined intervals to prospectively track SFPN patients with various causes being treated in different ways, and will also follow untreated SFPN patients to gather the first natural history data about early-onset SFPN. This should provide the information needed to plan for future clinical trials of promising treatments.